Vibratome technique revealed initial carcinogenic changes that induce GST-P single hepatocytes and minifoci in rat liver.

The drastic initial carcinogenic changes that induce single hepatocytes and minifoci positive for GST-P (a specific biomarker of foci and nodules) identified previously in rat livers (K. Satoh, Life Sci. 2018) require elucidation.

Cilia-Mediated Insulin/Akt and ST2/JNK Signaling Pathways Regulate the Recovery of Muscle Injury.

Following injury, skeletal muscle regenerates but fatty tissue accumulation is seen in aged muscle or muscular dystrophies. Fibro/adipogenic progenitors (FAPs) are key players in these events; however, the effect of primary cilia on FAPs remains unclear. Here, it is reported that genetic ablation of trichoplein (TCHP), a ciliary regulator, induces ciliary elongation on FAPs after injury, which promotes muscle regeneration while inhibiting adipogenesis.

Aurora A and AKT Kinase Signaling Associated with Primary Cilia.

Dysregulation of kinase signaling is associated with various pathological conditions, including cancer, inflammation, and autoimmunity; consequently, the kinases involved have become major therapeutic targets. While kinase signaling pathways play crucial roles in multiple cellular processes, the precise manner in which their dysregulation contributes to disease is dependent on the context; for example, the cell/tissue type or subcellular localization of the kinase or substrate. Thus, context-selective targeting of dysregulated kinases may serve to increase the therapeutic specificity while reducing off-target adverse effects.

Primary cilia and lipid raft dynamics.

Primary cilia, antenna-like structures of the plasma membrane, detect various extracellular cues and transduce signals into the cell to regulate a wide range of functions. Lipid rafts, plasma membrane microdomains enriched in cholesterol, sphingolipids and specific proteins, are also signalling hubs involved in a myriad of physiological functions. Although impairment of primary cilia and lipid rafts is associated with various diseases, the relationship between primary cilia and lipid rafts is poorly understood.

Indispensable role of Galectin-3 in promoting quiescence of hematopoietic stem cells.

Hematopoietic stem cells (HSCs) in adult bone marrow (BM) are usually maintained in a state of quiescence. The cellular mechanism coordinating the balance between HSC quiescence and differentiation is not fully understood. Here, we report that galactose-binding lectin-3 (galectin-3; Gal-3) is upregulated by Tie2 or Mpl activation to maintain quiescence.

Primary cilia-dependent lipid raft/caveolin dynamics regulate adipogenesis.

Primary cilia play a pivotal role in signal transduction and development and are known to serve as signaling hubs. Recent studies have shown that primary cilium dysfunction influences adipogenesis, but the mechanisms are unclear. Here, we show that mesenchymal progenitors C3H10T1/2 depleted of trichoplein, a key regulator of cilium formation, have significantly longer cilia than control cells and fail to differentiate into adipocytes.

Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer.

Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause various diseases, including cancer and ciliopathies, which are complex disorders caused by mutations in genes regulating ciliary function.

Visualization of Proliferative Vascular Endothelial Cells in Tumors in Vivo by Imaging Their Partner of Sld5-1 Promoter Activity.

Vascular endothelial cells (ECs) isolated from tumors characteristically express certain genes. It has recently been suggested that tumor vessel normalization facilitates effective drug delivery into tumors; however, how tumor vessel normalization can be recognized on the basis of the molecules expressed by tumor ECs is not clearly defined. The degree of cell proliferation is an important indicator to characterize the condition of the ECs.

Elevated expression of Tie1 is accompanied by acquisition of cancer stemness properties in colorectal cancer.

The Tie receptors 1 and 2 (Tie1/2) play crucial roles in embryonic angiogenesis. Recent studies suggest enhanced expression of Tie1 in several types of cancer and negative correlations between Tie1 levels and clinical outcome. These observations suggest important functions of Tie1 not only for vascular formation but also in tumorigenesis.

Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy.

Antiangiogenic agents transiently normalize tumor vessel structure and improve vessel function, thereby providing a window of opportunity for enhancing the efficacy of chemotherapy or radiotherapy. Currently, there are no reliable predictors or markers reflecting this vessel normalization window during antiangiogenic therapy. Apelin, the expression of which is regulated by hypoxia, and which has well-described roles in tumor progression, is an easily measured secreted protein.

APJ Regulates Parallel Alignment of Arteries and Veins in the Skin.

Molecular pathways regulating the development of arterial and venous endothelial cells (ECs) are now well established, but control of parallel arterial-venous alignment is unclear. Here we report that arterial-venous alignment in the skin is determined by apelin receptor (APJ) expression in venous ECs. One of the activators of APJ is apelin.

An angiogenic role for adrenomedullin in choroidal neovascularization.

Purpose: Adrenomedullin (ADM) has been shown to take part in physiological and pathological angiogenesis. The purpose of this study was to investigate whether ADM signaling is involved in choroidal neovascularization (CNV) using a mouse model.

Methods And Results: CNV was induced by laser photocoagulation in 8-week-old C57BL/6 mice.

Ligand-independent Tie2 dimers mediate kinase activity stimulated by high dose angiopoietin-1.

Tie2 is a receptor tyrosine kinase expressed on vascular endothelial cells (ECs). It has dual roles in promoting angiogenesis and stabilizing blood vessels, and it has been suggested that Tie2 forms dimers and/or oligomers in the absence of angiopoietin-1 (Ang1); however, the mechanism of ligand-independent dimerization of Tie2 and its biological significance have not been clarified. Using a bimolecular fluorescence complementation assay and a kinase-inactive Tie2 mutant, we show here that ligand-independent Tie2 dimerization is induced without Tie2 phosphorylation.

Galectin-3 accelerates M2 macrophage infiltration and angiogenesis in tumors.

It is widely accepted that robust invasion of tumor-associated macrophages resembling M2 macrophage correlates with disease aggressiveness by affecting cancer cell invasion, metastasis, and angiogenesis. Many chemokines that induce migration of macrophages have been identified during inflammatory responses; however, further precise analysis of macrophage migration in the tumor microenvironment is required. Here, we analyzed the function of galectin-3 (Gal-3; gene LGALS3, alias Gal3) for macrophage chemotaxis using Gal3(-/-) mice as hosts, and a tumor allograft model.

Nonclonal growth of preneoplastic cells positive for glutathione S-transferase P-form in the rat liver.

We investigated the process of induction of preneoplastic cells positive for glutathione S-transferase P-form (GST-P) in the rat liver. AAF (2-Acetylaminofluorene) mixed with normal rat chow at high concentration (0.04%) induced 517 000 ± 86,000 GST-P(+) single hepatocytes/g liver after 2 weeks followed by induction of a few foci and nodules after 4-6 weeks.

2-Methoxycinnamaldehyde inhibits tumor angiogenesis by suppressing Tie2 activation.

Blood vessels are mainly composed of intraluminal endothelial cells (ECs) and mural cells adhering to the ECs on their basal side. Immature blood vessels lacking mural cells are leaky; thus, the process of mural cell adhesion to ECs is indispensable for stability of the vessels during physiological angiogenesis. However, in the tumor microenvironment, although some blood vessels are well-matured, the majority is immature.

Lipid rafts serve as signaling platforms for Tie2 receptor tyrosine kinase in vascular endothelial cells.

The Tie2 receptor tyrosine kinase plays a pivotal role in vascular and hematopoietic development. The major intracellular signaling systems activated by Tie2 in response to Angiopoietin-1 (Ang1) include the Akt and Erk1/2 pathways. Here, we investigated the role of cholesterol-rich plasma membrane microdomains (lipid rafts) in Tie2 regulation.

Bile duct-bound growth of precursor cells of preneoplastic foci inducible in the initiation stage of rat chemical hepatocarcinogenesis by 2-acetylaminofluorene.

Background: We previously detected precursor cell populations of preneoplastic foci, GST-P(+)/GGT(-) and GST-P(+)/GGT(+) minifoci, in rat liver in the initiation stage of chemical hepatocarcinogenesis, where GST-P and GGT represent glutathione S-transferase P-form and gamma-glutamyltranspeptidase, respectively.

Methods: Sprague-Dawley male rats were fed a basal diet containing 2-acetylaminofluorene (0.02%) over 16 weeks.